The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-9277, USA.
Am J Ophthalmol. 2013 Apr;155(4):697-704, 704.e1-2. doi: 10.1016/j.ajo.2012.09.032. Epub 2012 Dec 4.
To evaluate the safety and bioactivity of MP0112, a designed ankyrin repeat protein (DARPin) that specifically binds vascular endothelial growth factor (VEGF) in patients with diabetic macular edema (DME). DARPins are a novel class of proteins selected for specific, high-affinity binding to a target protein.
Phase I/II, open-label, multicenter dose-escalation trial.
After a single intravitreal injection of MP0112, the main outcomes were safety assessments, aqueous MP0112 levels, change in best-corrected visual acuity (BCVA), and foveal thickness measured by optical coherence tomography. Six cohorts were planned, but only 3 were enrolled (0.04, 0.15, 0.4 mg), because a maximally tolerated dose of 1.0 mg was identified in a parallel age-related macular degeneration trial.
Median aqueous concentration of MP0112 was 555 nM 1 week and >10 nM in 3 of 4 patients 12 weeks post injection of 0.4 mg. Median BCVA improvement at week 12 was 4, 6, and 10 letters in cohorts 1, 2, and 3. Ocular inflammation was observed in 11 patients (61%) and was severe in 1. High-resolution chromatography separated proinflammatory impurities from MP0112, resulting in a new formulation.
A single intraocular injection of 0.4 mg MP0112 resulted in levels above the half-maximal inhibitory concentration and neutralization of VEGF in aqueous humor for 8-12 weeks. Despite inflammation in several patients, there was prolonged edema reduction and improvement in vision in several patients. The source of the inflammation was eliminated from a new preparation that is being tested in an ongoing clinical trial.
评估 MP0112（一种特异性结合血管内皮生长因子[VEGF]的设计锚重复蛋白[DARPin]）在糖尿病黄斑水肿（DME）患者中的安全性和生物活性。DARPins 是一类新型蛋白，经选择可特异性、高亲和力地结合靶蛋白。
I/II 期、开放标签、多中心剂量递增试验。
单次玻璃体内注射 MP0112 后，主要观察终点为安全性评估、房水中 MP0112 水平、最佳矫正视力（BCVA）变化和光学相干断层扫描测量的中心凹厚度。计划设 6 个队列，但仅纳入 3 个队列（0.04、0.15、0.4mg），因为在平行的年龄相关性黄斑变性试验中确定了 1.0mg 的最大耐受剂量。
玻璃体内注射 0.4mg 后 1 周时 MP0112 的中位房水浓度为 555nM，4 例患者中有 3 例在 12 周时仍＞10nM。12 周时，队列 1、2 和 3 的中位 BCVA 改善分别为 4、6 和 10 个字母。11 例（61%）患者出现眼内炎症，1 例为重度。高分辨率色谱将促炎杂质与 MP0112 分离，形成新的制剂。
单次玻璃体内注射 0.4mg MP0112 可使房水中的药物水平保持在半数最大抑制浓度以上，并中和 VEGF 长达 8-12 周。尽管一些患者出现炎症，但一些患者的水肿仍持续减轻，视力改善。炎症的来源已从正在进行的临床试验中测试的新制剂中消除。
